Marta Cascante
Cascante, Marta
University of Barcelona
Barcelona, Spain
Title: Systems Biology in multifactorial diseases
Authors: Marta Cascante, Igor Marin, Miriam Zanuy, Santiago Diaz-Morelli, Susana Sanchez, AdriĆ  Benito, Carlos Ciudad, Josep Centelles, Gema Alcarraz, Tatyana Votyakova, Josep Roca, Silvia Marin, Vitaly Selivanov
Abstract:Metabolomics allows direct measurement of multiple low-molecular-weight metabolites from a biological sample. Metabolome of an organism is the result of the in vivo function of gene products and is, is closely tied to its physiology and its environment. Thus, while transcriptomics and proteomic analysis do not tell the whole story of what might be happening in a cell, metabolomics offers a unique opportunity to look at relationships between genotype and phenotype as well as with environment. However, knowledge of the complete set of metabolites is not enough to predict the phenotype. Therefore, for a comprehensive characterization of metabolic networks and their functional operation quantitative knowledge of intracellular metabolic fluxes is required. These intracellular fluxes can be estimated through quantitative measurements of metabolites at different times and/or incubation of cells/organisms with labeled substrates and interpretation of stable isotope patterns using appropriate software packages.

By using this strategy we have identified that maintenance of oxidative-nonoxidative pentose phosphate pathways unbalance is critical for angiogenesis and cancer cell survival and vulnerable to chemotherapeutic intervention. Moreover, we have used Metabolic Control Analysis (MCA) to design combined target strategies, which have been validated by using specific inhibitors. This strategy results of great interest for the study of other multifactorial diseases. In particular, its application to achieve a better understanding of glucose metabolic network and respiratory chain to design interventions at a metabolic level in chronic obstructive pulmonary disease (COPD), has permitted us to identify bistability inherent to complex III operation which explain high ROS production in hypoxia-reoxygenation processes.

We concluded that a fully understanding of the metabolic adaptation accompanying multifactorial diseases as cancer or COPD open new ways to develop novel multi-hit therapies which works on attacking several pathways simultaneously.

This work was supported by funds of Spanish Government and European Union FEDER SAF2008-00164; ISCIII-RTICC (RD06/0020/0046); European Comission BIOBRIDGE (LSHG-CT-2006- 03793-FP6,DIAPREPP (FP7-202013) and ETEHRPATHS (FP7-222639); and Generalitat de Catalunya (2005SGR00204 and 2009SGR-1308).

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